Fluid flowing device and method for tissue diagnosis or therapy

ABSTRACT

A device and method for safely securing a multilumen device to a tissue, organ or solid tumor within the body of a human during a diagnostic or therapeutic procedure is described. The device is capable of securing the tumor by touching or piercing its surface and providing a coolant to the distal tip. Cooling the tip forms a cryogenically induced region that tightly binds the tip to the tumor, temporarily sealing the entry-track of the instrument. The device further provides at least one injecting/aspirating lumen that can dispense or aspirate a fluid within the tumor, and an outer sheath or guide. Such construction allows injecting part or whole volume of the tumor while the cryogenically induced bond prevents back-flow of the injected substances through the entry-track.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part and claims priorityunder 35 U.S.C. §120 to U.S. Patent Application 12/182,472, which claimsthe benefit of the filing date of U. S. Provisional Patent ApplicationNo. 60/962,465, filed on Jul. 30, 2007 the contents of which areincorporated herein by reference; and claims the benefit of priorityunder 35 U.S.C. §119(e) to U.S. Provisional Patent Application No.61/171,713, filed Apr. 22, 2009, the contents of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to fluid delivery devices and methods fordelivering direct tissue injection/aspiration to tissue structureswithin the body. More specifically, the invention relates to aself-anchoring, anti-flow back device capable of securing to a targetedtissue region during diagnostic and/or therapeutic procedures whilefurther providing for optimal injection of compositions to the targettissue structure and the methods of use thereof.

BACKGROUND OF THE INVENTION

Direct deposition of agents interstitially can be of significantbeneficial value and is effected by needle or catheter use. Tissueinjection has long been a popular, relatively non-invasive means for thedirect introduction of various medicaments and other fluids. It isbecoming more popular as a means for non-invasive delivery ofpharmaceutical preparations of cytotoxic drugs and drug delivery systemsinto solid tumor because it minimizes tissue trauma, increases localefficacy, and decreases side effects and systemic toxicity. Directinjection, using needles, catheters, or a combined deposition system, isa practical delivery strategy for antiangiogenesis, tumor embolization,hemostasis, and direct cell kill. Direct interstitial chemotherapy isslowly gaining ground among the medical community. A growing number ofresearch papers and clinical reports published during the years1990-2000 have shown improved efficacy and reduced toxicity in animal aswell as in human tumors (E. P. Goldberg et al., J. Pharm Pharmacol54(2):159-180 (2002)).

Most commercial injection systems use needles or catheters which areincapable of preventing backflow of fluid out of the entry-track. Thesesystems suffer from the difficulties associated with lack of a steadymeans of securing to a target. Current securing and anti backflowinjecting systems described in the literature are either too aggressiveto tissues or do not insure tight and steady bonding. In addition,injection techniques are operator dependant. Such techniques rely uponperceived tumor margins and mass, subjective assessment of the number ofsites of puncture to cover the entire visible mass, and subjectiveassessment of the liquid-dose fraction to inject at each site. Relyingupon commercial needles or catheters, the operator must inject each sitewith a fraction of the calculated dose at a rate which insures a“homogeneous” distribution and deposition of the agents. In addition,needle tips that do not remain steady during injection results inpuncturing or injecting unwanted structures.

Needles used in injection systems most often contain a pointed endhaving a single orifice. This type of needle does not allow for acontrolled distribution of an agent, such as a fluid or a particle,within the interstitial medium of the target. Necrotic zones of thetumor as well as the tumor vasculature should be spared. Therefore,agent distribution within a tumor is random and based on uncontrollableconvective forces or on perceived tumor “capacitance” for fluidabsorption (subjective fill counter pressure, late visualization offluid backflow that most often cannot be prevented). Similarly, completedose administration is not guaranteed since backflow cannot beprevented, is difficult to assess, and intravascular administration isnot easy to detect. Multiplying the sites of injection or usingmulti-needle injectors not only increases the probability of injury totumor structures but also increases the operation time. Moreover, thistype of procedure can lessen a patient's tolerance, leading to decreasein patient compliance to repeated procedures.

Current tissue delivery systems for depositing fluid or fluid-likeagents and fluid based substances into an entire lesion utilizesmultiple needle tips repeatedly inserted into the tissue in order toincrease the diameter of induced necrosis/apoptosis. This approach,however, is both time-consuming and difficult to employ in the clinicalsetting particularly because multiple overlapping treatments must beperformed in a contiguous fashion in order to distribute the agent tothe entire lesion. Simultaneous use of multiple needles can reduce theduration of application but is difficult for use in narrow passages orendoscopically since it is technically challenging. The development ofpronged injection needle electrodes with multiple arrays should enablethe creation of larger foci of more homogeneous fluid distribution witha single penetrating site.

In spite of the promise associated with most techniques of directinterstitial fluid-based therapies such as chemoablation of skin, lung,prostate, breast, head and neck, brain tumors, liver tumors, and thepotential clinical applications of these techniques, progress has beenhampered by the lack of effective means to achieve the overall objectiveof efficient and reliable agent delivery to target. One of the mostsignificant shortcomings related to the current systems is the inabilityto achieve reliable and consistent application from subject to subject.Moreover, insuring full dosage of a therapeutic agent administered tothe target lesion can not be guaranteed. Significant sources of thisvariability are due to differences in the technique and skill level ofthe operator as well as differing physiological characteristics betweenpatients.

Even if the dose amount of agents injected locally into a tumor tissueis usually much lower than systemic administration, low dosage isdesirable in order to prevent side effects. Preventing compositionflowing out of the target area is critical, as back flow of the agentscan result in unintended harm to healthy structures, createcomplications, or prolong the procedure. The instantly disclosed systemand method has the potential of fast and reliable securing method andmore efficient delivery and diffusion of the calculated dose ofcomposition directly into the target tissue through a single injectionsite, while preventing backflow of injected composition through theentry track of the instrument.

DESCRIPTION OF THE PRIOR ART

The minimally invasive and non-aggressive securing of operativeinstruments (biopsy, needle, and probe) to tissue using a negativepressure cannula has been described in several U.S. Pat. No. 7,128,738,discloses a system and method of treating fibroadenomas using aminimally invasive cryosurgical procedure. The procedure entails use ofa cryoprobe to ablate a fibroadenoma. The cryoablation procedure uses acryoprobe adapted to perform a period of high power freezing, followedby a period of low power freezing. Such high powered freezing and lowpowered freezing is followed by a period of thawing, and a repetition ofhigh power freezing and low power freezing, followed by thawing and/orwarming of the cryoprobe.

U.S. Pat. No. 6,494,844 and related application U.S. Pat. No. 6,945,942describe a system and methods for diagnosis and treatment of breasttumors within the breast. The devices include structures which allow asurgeon to secure a mass or tumor within the breast for an extendedperiod of time and for several biopsies, coring procedures, orresections. The tumor is secured to a cannula through the use of avacuum where a biopsy needle is used to retrieve a tissue. Use of acryoprobe inserted into the cannula for ablation treatment is disclosed.

U.S. Pat. No. 6,540,694, and related U.S. Pat. Nos. 6,551,255 and7,311,672, describe devices and methods of use for securing and coringof tumors within the body. The devices include an adhesion probe whichsecures the tumor to the probe by use of a coolant. The device furtherincludes a coring instrument. Upon securing of the probe to the tumor, asurgeon retrieves a sample by cutting a core sample from the tumor.

U.S. Pat. No. 7,402,140 describes a device for diagnosing tumors. Thedevice includes an adhesion probe which provides securing of a tumor tothe probe during surgical procedures by use of coolant. The coolant isdirected to the distal tip of the apparatus through a rigid tube,thereby cooling the tip. The device further includes a coring apparatushaving a cannula and a means for rotating and translating the cuttingcannula.

Although such patents may teach the use of a cryogenic probe for coringand/or cryosurgically ablating a target tissue through the securingcannula none of the prior art teaches an apparatus capable of producingminimal and/or sizeable cryogenically induced regions sufficient tominimize or prevent backflow of injected fluids through an entry trackfrom an associated injection device for fluid-based diagnosis or therapyof a target tissue.

SUMMARY OF THE INVENTION

Given that reliable and consistent application of clinical therapies ofdirect intratissue injection is highly desirable, the development ofimproved application systems is well warranted. Such development shouldinclude a means for minimizing operator-associated variability, such asprocedural safety and efficacy, while providing a means to accommodatethe differences in tumor and patient characteristics likely to beencountered during widespread clinical application of fluid-basedinterstitial therapies used as the sole treatment or in conjunction withloco-regional or systemic therapies.

The present invention is generally characterized by a multilumencatheter including at least one lumen for supply of a cryogenic materialwherein the lumen is in fluid connection with at least one cryogenicelement effective for lowering at least a portion of the tissuestructure in a range near its freezing point. The device also containsat least one lumen for delivery of said treating composition. Themultilumen catheter is constructed and arranged for supplying at leastone composition to a treatment region within a tissue structure inconjunction with to supplying of cryogenic material. Supplying ofcryogenic material results in at least one cryogenically induced regionformation, or cryoseal, which is effective to minimize or preventbackflow of the treating composition. The use of cryoseal according tothe invention is defined as defined as a cooled biological interfacelayer made of frozen and/or unfrozen target tissue layers that developabout the cooling zone of the device. The cryoseal can be formed in anyshape, but preferably ring-shaped, and temporarily prevents fluids fromescaping through the entry-track of the delivery instrument to thetarget tissue and prevents fluids from flowing back through it.

When the apparatus' distal end is immersed into the tissue and thecryoseal is formed, it is possible to inject a composition distal to thecryoseal without creating backflow of the injected composition throughthe entry track of the apparatus, despite the high hydrostatic pressurethat the tissue is under. Under similar circumstances, the currentinvention further discloses a fluid aspiration element capable ofaspirating fluids, or fluid components, from the tissue and/orsurrounding area for diagnostic purposes.

A plurality of distal end designs allow for multipleinjection/aspiration openings, and/or multiple cooling members. Therelative proximal and/or distal location of the openings with respect tothe cryoseal may vary dependent upon use within plain or hollow organ.

The composition injection system may include a thermal element forheating or cooling the composition and a metered syringe or pump thatallows injecting interstitially, manually or automatically, preciselymeasured amounts of composition at selected temperature directly into abody tumor or tissue.

The present invention includes a method and apparatus for transientsealing of the entry track of an injection instrument, and securing theinstrument into a tissue during fluid-based diagnostic and/ortherapeutic applications.

The present invention pertains generally to an apparatus and a method ofuse to deliver compositions, such as a substance/drug, directly to orinto intact or damaged biological tissue, such as normal, benign ormalignant tumor, organ, or body structure of an animal or a human. Theinvention pertains to a cryogenic fluid and composition delivery systemand method that allows reversible and/or innocuous adherence of thedelivery tip to a tissue target. The invention pertains to a cryogenicfluid and composition delivery system that provides self-adherence,substance injection/infusion into tissue, and prevention ofbackflow/outflow of injected substances through an entry track ofsystem.

The present invention may use sensors to monitor procedures, such asthermal, bioelectrical, sonic, or photonic sensors. Performance of themethod is facilitated by a control system that allows an operator or atechnician to deliver and control initiation, growth, maintenance, andregression of the reversible, biologic cryogenic seal. The controlsystem may further be used to manage concurrent positioning of fluidinjection openings which allows for a selected amount of substance to beinjected into pervious regions of the target tissue or lesion. Afterentry of these parameters, the system operates automatically to applycooling to maintain the sealing frozen/unfrozen layer during delivery ofcompositions to the tissue. The location of the delivery tip as well asinjection of compositions may be monitored using imaging devices such asultrasound, CT, MRI, and sensors, etc.

The present system uses cryogen gas and/or liquid to generate theformation of a frozen/unfrozen layer at the interface between the tissueand the entry track of a diagnostic and/or therapeutic tool that isdirectly introduced into the target tissue. In the first step, thedistal end of the device is guided to the tissue structure usingappropriate guiding means. The working end is embedded into a treatmentregion, such as a tumor, through the tissue surface at a desirable depthand, if necessary, imaged by an external device, such as ultrasound orassessed by sensors. The working end may be made “echogenic” by variousknown mechanical or chemical coatings, treatments, or alternatively byvibrating it at specific low (sonic) frequencies induced by a driver(COLORMARK and NUVUE COLORMARK, NuVueTherapeutics, Inc). Cryogenic fluidis applied to the device, allowing fluid expansion within the lumen atthe distal end and providing a cryogenically induced region effective tominimize or prevent back flow. In conjunction with formation of thecryoseal, injection of compositions commences. Formation of the cryosealis assessed by immobilization of the tip end within the tissue orthrough measuring means, such as direct measuring of thering-shaped-to-tissue interface temperature or through calculation byspecific software. The cryogenically induced region is left to warmspontaneously or automatically or through guidance of the operator,resulting in melting of the cryoseal as soon as injection is complete ordesired. On spontaneous warming, detachment of the device occurs when itbecomes movable within the tissue or at a temperature above the tissuefreezing temperature.

The present system may further be built into the working end of anydelivery instrument of energy, fluid, gas, solid particles, cell, genes,and/or mixtures thereof. The system allows the instrument to secureitself steadily to the tissue and to seal the entry track of thedelivery tip of the instrument so that any substance and/or druginjected into the tissue can not flow back and leak out of the entrytrack, during or after the procedure. In addition, the present inventionfurther provides for injection of the compositions at any locationwithin the target tissue and/or within or near the cryothermalbiological seal.

The present system enhances deposition, distribution, and retention ofinjected compositions into the target tissue, while minimizing the riskof side effects due to under or overdosing, random distribution ofsubstance or leakage of injection fluid into unwanted tissue orstructure.

The present system involves using delivery instruments and methods thatcontact and/or penetrate tissue such as a needle, catheter, probe andthe like, whose outer wall may lower the tissue temperature to under itsfreezing point while providing for internal structure that allowsdelivery of compositions to the tissue.

Applications involve direct access to superficial normal or tumor(benign or malignant) tissue, to superficial or deep tissue structure orlesion through natural cavity, or open surgery, through skin, or throughvascular network, or within endoscope.

The present system and method may be used for fluid-based diagnosis oftissue nature by aspirating tissue fluids or components. A procedureusing the system may include a diagnosis step followed by a therapeuticstep.

In a preferred method of this invention, the fluid composition injectionis set to be effected during the formation of the bonding and occludingof the sizeable frozen/unfrozen layer (cryoseal). It is contemplatedwithin the invention that the cryoseal can be executed first tomanipulate the lesion. Injection can be performed after desirablepositioning and handling of the lesion. It is also contemplated thatinjection of the compositions can occur prior to, concurrently with, orafter the formation of, during and after the cryoseal to minimize theflow back of injected substance.

It is further contemplated that composition injection openings at thedistal end of a needle or catheter tip are distally located with respectto the cooling zone. Alternatively the openings may be proximallylocated with respect to the cooling zone of the tip. During formationand maintenance of the cryoseal, the compositions are pushed at adistance from the cryoseal, and do not compromise the sealing effect ofthe cryoseal. It is further contemplated that the fluid injectionopenings can be positioned anywhere within the target tissue to adjustto various cryoseal shapes, dimensions, various ratios of frozen tounfrozen interfaces, or pervious to impervious interfaces.

It is also contemplated by the invention that a direct tissue injectionsystem and method can be associated with any indicated local, regionaland/or systemic therapy.

The invention further relates to an enhanced tissue injection andself-anchoring system that has the potential to lower the dose ofsubstances administered locally. The invention further relates to anapparatus, system and a method that has the potential to reduce theduration of application/operation, reduce the number of injection sitesand applications, reduce the total dose administered, and increase thesafety and effectiveness of direct fluid-based tissue diagnostic and/ortherapeutic procedures.

In accordance with this invention, the term “Cryoseal” is defined as acooled biological interface layer made of frozen and/or unfrozen targettissue layers that develop about the cooling zone of the device. Thecryoseal can be formed in any shape, but preferably ring-shaped, andtemporarily prevents fluids from escaping through the entry-track of thedelivery instrument to the target tissue and prevents fluids fromflowing back through it.

In accordance with this invention, the term “composition” is defined asa substance or mixture of two or more substances, inert or activeagents, compositions, such as but not limited to, individual orcombinations of free, formulated, or encapsulated drugs, compounds,contrast agents, biologically active peptides, genes, gene vectors,proteins, or cells for therapy, into the tissues or cells of a human oranimal patient. The active agents, include but are not limited to,saline solution, heating or cooling fluids, photosensitizer,radiosensitizer, radioisotopes, sclerosants (sclerosing agent),radioseeds, thermoseeds, glue, vaccines, genes, immunologic factors,hormones, particles, nano-particles, and combinations/formulationsthereof.

It is contemplated that for the purpose of tissue kill, compositionsthat act directly on cells and/or indirectly on tissue structure andmore particularly on their vascular bed would be best suited. Althoughdirect intralesional therapy is well suited for injection of a fluidcomposition it will be understood by those skilled in the art that othercompositions, such as, for example, viscous compounds, semi-fluids, orsolids in granular or powdered form may also be injectable. Furthermore,the compositions may be injected in a liquid state and, after injection,solidify under the influence of body heat or by the application of anexternal energy source, such as, for example, microwave, radio frequencyor electromagnetic energy. Alternatively, a solid or semisolidcomposition may be injected, and, after injection, liquefy under theinfluence of body heat or an external energy source.

As used herein with reference to supplying at least one composition to atreatment region within the tissue structure, “in conjunction with” isdefined to include injection of the compositions prior to, subsequentto, or concurrently with supplying of cryogenic material.

In accordance with this invention, the term “liquid refrigerant andrefrigeration system,” “cryogenic material,” “cryogenic fluid,” and“cryogenic agents” are used interchangeably and refer to the coolant forthe system and/or the system itself (i.e. tubing, containers,connectors, control systems and interconnections thereof). The coolantis defined and may be a mixture of one or more coolants at high or lowpressure. Cryogenic materials include, but are not limited to,chloroform, ether, fluorocarbon refrigerant R134, liquid air, liquidargon, liquid butane, liquid carbon dioxide, liquid DYMEL blend, liquidhelium, liquid nitrogen, liquid oxygen, liquid propane, liquidrefrigerant compounds and other coolant formulation known from those whoare expert in the art. Preferred refrigerant for the system may be R134or liquid CO₂, from any kind of cylinder or cartridge. The cylinder orcartridge can be either disposable or re-usable. Alternatively,cryogenic materials may be cooled saline at low temperature flowingthrough a pump-flow regulator system. Consumption of the coolant isminimal and cooling principles used are simple such as change of phaseor gas expansion, requiring low cost manufacturing and allowing fordisposable single use injector. Added advantages of using low-pressuregas coolant include is lack of need for costly materials or highcomplexity of testing for safety systems which required forhigh-pressure gas operated systems.

In accordance with this invention, “Fluid-based diagnosis” is defined asinjection of a fluid that allows discrimination and determination of thetissue nature and characteristics or aspiration of tissue fluidcomponents, including cells or tissue structures, for analysis.

Accordingly, it is a primary objective of the instant invention toprovide a system and method for diagnosing and/or treating targettissues, particularly solid tumors, by aspirating and/or injecting acomposition into the target tissue.

It is a further objective of the instant invention to provide a deviceand a method for treating target tissues by injecting a compositionwhile minimizing exposure of healthy tissue to the composition.

It is yet another objective of the instant invention to provide anapparatus with low profile design and smooth surface to penetrate tissuewith minimal tissue trauma.

It is a still further objective of the invention to provide an apparatuswith tissue anchoring and securing cryogenic means before, during and/orafter injection resulting in easier, faster injection procedures, lessrisk of unwanted displacement of an indwelling instrument, and minimalrisk of injection of composition to non-targeted tissue structures.

It is another object of the invention to provide an apparatus withcryogenic means for stabilization and steadiness before, during and/orafter aspiration resulting in improved aspiration procedures, less riskof unwanted displacement of an indwelling instrument, and minimal riskof procedural complications.

It is another object of the invention to provide an apparatus with meansto prevent backflow of injected composition along the tissue entry trackof the instrument.

It is another object of the invention to provide an apparatus with meansto inject and prevent back flow of a composition through a single entrytrack and prevent back flow of composition while using the entry trackfor injection to minimize trauma to the tissue.

It is another object of the invention to provide an apparatus with meansto inject and prevent back flow of a composition through a single entrytrack and prevent back flow of composition while injecting the necessarydose of composition within low compliant target and/or against naturallyor artificially elevated interstitial target tissue pressure.

It is another object of the invention to provide an apparatus with meansto prevent back flow of fluid from tissue in combination with a means toaccommodate various instruments for diagnostic or therapeutic purpose,including interstitial fluid injection/aspiration therapies and/orinterstitial energy-based devices, such as thermal, sonic, lightablation, or electroporation.

It is another object of the invention to provide an apparatus with highor low-pressure refrigerant means so that construction is simplified,cost is reasonable and procedural risks are minimized.

It is a further objective of the instant invention to provide anapparatus with the capability of preventing back flow of fluid from atissue target area and which utilizes a coaxial sheath or guide.

It is a further objective of the instant invention to provide for amethod for treating target tissues by injecting a composition whileminimizing exposure of healthy tissue to the composition, the methodutilizing an apparatus with the capability to prevent back flow of fluidfrom a tissue target area and which contains a coaxial sheath or guide.

Other objects and advantages of this invention will become apparent fromthe following description taken in conjunction with any accompanyingdrawings wherein are set forth, by way of illustration and example,certain embodiments of this invention. Any drawings contained hereinconstitute a part of this specification and include exemplaryembodiments of the present invention and illustrate various objects andfeatures thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a longitudinal sectional view of the distal end of thecatheter element embedded into the treatment region of a tissuestructure.

FIG. 1B is a cross section taken along the line 1B-1B of FIG. 1.

FIG. 2 is an alternative embodiment of the invention, illustratingformation of multiple cryogenically induced regions that delineate aregion for deposition, diffusion, and retention of injected compositionswithin a hollow organ.

FIG. 3 is a perspective view of a self-anchoring andinjection/aspiration system for delivering a treatment composition to atissue structure, in accordance with an embodiment of the invention.

FIG. 4A is an embodiment of the multilumen catheter, illustrating onelumen in slidable connection with the outer surface of the catheter andin parallel relationship with the lumen in fluid connection with acryogenic element.

FIG. 4B is a cross section taken along the line 4B-4B of FIG. 4A.

FIG. 4C illustrates an additional embodiment of the multilumen catheterin which one lumen is in slidable connection with the outer surface ofthe catheter and in a parallel relationship. As opposed to FIG. 4A, theembodiment illustrated in FIG. 4C shows the cryogenic probe capable ofmovement relative to the injecting lumen.

FIG. 5A is a longitudinal section of a self-anchoring cannula whoseoperative channel accommodates various applicator(s) or guide(s).

FIG. 5B is an expanded view of the distal portion of the catheter asexemplified in FIG. 5A, illustrating multiple, variable lengthapplicators.

FIG. 6A is a longitudinal sectional view of the distal end of thecatheter element retracted into the outer coaxial sheath.

FIG. 6B is a cross section taken along the line 6B-6B of FIG. 6A.

FIG. 6C is a longitudinal sectional view of the distal end of thecatheter element, illustrating the distal end protruding from the outersheath member.

FIG. 6D is a longitudinal sectional view of the multilumen catheter andouter sheath embodiment, having two cryogenically induced regions.

FIG. 6E illustrates another embodiment in which the outer sheathcontains a cryogenic fluid lumen.

DETAILED DESCRIPTION OF THE INVENTION

Methods, systems, and apparatus according to the present invention relyon placement and use of one or more anchoring and injection/aspirationelements positioned at or within a treatment region of a patient. Thetreatment region may be located anywhere in the body where fluidinjection/aspiration may be beneficial. Most commonly, the treatmentregion will comprise a solid tumor within an organ of the body, such asthe liver, kidney, lung, bowel, stomach, pancreas, breast, prostate,uterus, muscle, brain. The volume of fluid-based substance to beinjected depends on the size of the tumor or other lesion, typicallyhaving a total volume from 1 cm.³ to 150 cm.³, usually from 1 cm.³ to 50cm.³, and often from 2 cm.³ to 35 cm.³. The peripheral dimensions of thetreatment region may be regular, e.g. spherical or ellipsoidal. However,typical tumor shape is irregular. The treatment region may be identifiedusing conventional imaging techniques capable of elucidating a targettissue, e.g. tumor tissue, such as ultrasonic scanning, magneticresonance imaging (MRI), computer-assisted tomography (CAT),fluoroscopy, nuclear scanning (using radio labeled tumor-specificprobes), and the like. High-resolution ultrasound or CT can be employedto monitor the size and location of the tumor or other lesion beingtreated, intraoperatively or externally.

The treatment region may also be identified with sensors for sensingtissue parameters such as electrical impedance, temperature, pressure,and optical characteristics disposed at the distal end of the indwellingself-anchoring catheter on injection/aspiration needle. One or moresensors may be used in any desirable combination and disposition overthe indwelling end of the self-anchoring catheter or needle.

In an illustrative embodiment, the present invention generally providesa tissue-anchoring, fluid delivery and aspiration system, and preferablya fluid delivery system for delivering cytotoxic drugs to theinterstitial space of solid tumor tissue. While the system can be usedfor a variety of purposes, it is preferably used to treat soft tissuetumors under ultrasound guidance in order to minimize exposure toradiation and reduce cost associated with the procedure. Although thepreferred embodiment describes a catheter-like device, it iscontemplated within the invention that the features described apply toneedle, cannulas, and other needle-like devices.

As illustrated in FIGS. 1A and 3, the self-anchoring, backflow limitingdevice includes a multilumen catheter member 10. Multilumen catheter 10has a proximal end 12, a distal end 13, an inner lumen 150 extendingthrough, and a cryogenically induced region (or anchoring member) 19. Atleast one cryogenically induced region and injection lumen includes ameans for occlusion of the instrument entry track into the tissue and aninjection opening 160 located at or distal to the cryogenically inducedregion. The multilumen catheter is comprised of a shaft 11. Inner lumen150 of the multilumen catheter 10 has adjacent multiple lumens (15, 16,17) as illustrated by FIGS. 1A and 1B.

The distal end 13 of catheter member 10 and/or the cryogenically inducedregion inner and/or outer wall 140 is optionally equipped with sensingmembers 18. Sensor members 18 are electrically coupled to a data logger(not represented), a controller, and monitoring system (notrepresented). The catheter 10 has fluid control means (aspiration,injection) at the proximal end 12 through tubing 120, and cryogenicfluid control means with controller 23 through tubing 230.

Quick connectors at proximal ends of tubing 120 and 230 allow for aninstant disconnection of the catheter member that is readilyinterchangeable and may be provided as a disposable element of theinvention. The distal end 13 of the catheter 10 may be steerable byconventional means. Alternatively, the distal end may be of aflexibility, toughness, and formability differing from that of shaft 11.The tip end 14 is preferably closed, blunt or tapered or round, but maybe of any desirable shape, flexibility and openness like pointed, sharp,cutting, fully open, pre-bent, or bendable, and/or steerable. Such metalas stainless steel, titanium, platinum or metallic alloy, or memorymaterial like nitinol may be used for its structure. Tip 14, or aportion thereof, may also be constructed of any material, such as butnot limited to radio opaque material, capable of being used forradiography or fluoroscopy purposes. Any desirable combination oftoughness, slidability, or flexibility and other desirablecharacteristics for the proximal end 12 and distal end 13 of catheter 10is within the spirit of the invention. Proximal end 12 has two extensionmembers 120 and 230; extension member 120 comprises two separate tubings121 and 122, see FIG. 3. Tubing 122 is coupled to inner lumen 17 ofcatheter 10 and more particularly to inner lumen 40 which fluidlycommunicates with opening ports 170 located at distal end 13 of cathetertip end 14. Tubing 121 fluidly communicates with inner lumen 16. Lumen16 is in fluid communication with opening port 160 at tip end 14.

Opening ports 160 and 170 are located distal to or at the level of thecryogenically induced region or anywhere along tip of distal end toallow for desirable injection-aspiration patterns. Opening ports 160 and170 may be located proximal to an cryogenically induced region whendistal end 13 comprises more than one cryogenically induced region

As illustrated in FIG. 3, the proximal end of tubing 121 is connected toa pressurized fluid source 22, for instances a syringe or a pump (notrepresented) well known to one of ordinary skill in the field. Thepressurized fluid source provides a means to inject, at a controlledrate and pressure, at least one fluid (composition and/or tissue fluid)of interest.

FIG. 3 also illustrates the proximal end of tubing 122 connections to avacuum source 21, for instances a syringe or a pump (not represented)well known to one of ordinary skill in the field. The vacuum sourceprovides means to aspirate, at a controlled rate and pressure, at leastone fluid (composition and/or tissue fluid) of interest.

It is contemplated that tubing 121, 122 and openings ports 160, 170 canbe used interchangeably as injection and/or aspiration members if theyare connected to the corresponding vacuum and pressurized sources thatcan be used sequentially or simultaneously through a manifold 50 (seeFIG. 3). For instances, a 4-way manifold (not detailed here) could allowfor a multiplicity of operations, including but not limited toaspirating fluids and waste, injecting, separately or in conjunction,composition and/or other desirable agents, such as but not limited tocontrast medium, hot or cold fluids, sealing substances. Moreover, asingle tubing can be used as an injection and aspiration means.

FIG. 2 illustrates an alternative embodiment of the invention. Inaddition to tumors, the multilumen catheter can also be used to treatareas of the body such as a vascular or organ lumen. As illustrated, themultilumen catheter is percutaneously introduced into vein lumen 211through vein wall 210. As further depicted, the multilumen catheter hastwo cryogenically induced regions 19′ and 19″ which can be formed bymultiple cryogenic lumens 15. The space 20 provides room for return ofthe cryogenic gas. Injection of a treatment composition, such as, butnot limited to a sclerosant, is accomplished through lumen 16. Theformation of the two cryogenically induced regions allows the substanceto remain at the site of deposition without being diluted or washed outby blood flow. Although the tip 14 is illustrated as being closed, it iswithin the invention that the tip also includes one or more openings.The formation of each cryoseal can be phased to alternate with eachother. Percutaneous approach and vascular access is made easier with theadjunct of the echogenic enhancement of the vibrating driver (COLORMARK& NUVUE COLORMARK, NuVueTherapeutics, Inc).

FIG. 4A illustrates another alternative embodiment of the invention,comprising a single tubing 16 and distal end opening 160, similar tothat of FIG. 1, along with a single cryogenically induced region 19proximal to opening 160. FIGS. 4A and 4B show injecting lumen 16 locatedparallel and adjacent and in slidable contact or arrangement (arrowindicating the direction of movement of single tubing 16 relative to thelumen 15) with the outer wall surface of catheter shaft 11 and distalend 13. Distal end opening 160 of lumen 16 is represented protruding offthe distal end of tip 14, illustrating a means for adjusting depth ofimmersion of distal end of injection/aspiration tubing 16 out of slidingchannel 161.

FIG. 4C illustrates yet another embodiment of the invention comprising asingle tubing 16 and distal end opening 160, similar to that of FIG. 1,along with multiple cryogenically induced regions 19′ and 19″. In orderto inject a composition without the effects of flow back, cryogenicallyinduced regions 19′ and 19 are formed such 191 is distal to opening 160and 19″ is proximal to opening 160. Comparable to the embodimentdescribed in FIGS. 4A and 4 B, this particular embodiment includes atleast two parallel lumens of which one of the lumens is in slidablecontact with the other. Unlike the previous devices, however, theembodiment shown in FIG. 4C illustrates a device in which the cryogenicprobe moves relative to injecting lumen 16. The cryoprobe element of themultilumen catheter, which includes inner lumen 15 for dispensingcryogenic material, is designed to be in parallel or coaxial, adjacentand slidable contact (arrow indicating the direction of movement) orarrangement with injecting lumen 16. In order to provide multiplecryogenic regions, inner lumen 15 contains multiple dispensing ends orsites, 15′ and 15″. The injecting lumen may contain a groove to allowfor guiding and sliding of the cryogenic probe.

The cryogenic element of the invention includes one or more cryogenicelements of the invention which play a role in providing the coolingeffect associated with the anti-flow back cryogenically induced region.As depicted in FIG. 3, extension member 230 of proximal end 12communicates with lumen 15 and 150 of distal end 13. Lumen 15 providescryogenic fluid at high or low pressure to chamber lumen 150 whosebottom defines level of wall 140 cooling zone and location ofcryogenically induced region interface (frozen/unfrozen layer). Thelocation of bottom wall 151 of chamber 150 defines the level, dimensionand shape of cryogenically induced region, thus resulting ranges of sizeand shape. The location of cryogenically induced region defines thelength of working member of catheter distal end 13.

Optional conduit 141 runs along shaft longitudinal axis within wallthickness of shaft 11 and may couple sensors (thermal, pressure,impedance) 18 with signal data loggers (not represented) throughelectrical wires, optical fibers, or any coupling cable for signaltransmission known to the field.

Extension member 230 is connected with a quick pneumatic/electricconnector 25 to controller 23 and to a cryogenic source gas cylinder 24.Although the cryogenic source 26 is illustrated as having a gas phase 27and liquid phase 28, any liquid refrigerant and refrigerant system iscontemplated for use within the invention. Gas cylinder 24 may contain acylinder valve 29.

Controller 23 contains modules for converting signals from sensors intoreadable parameters, such as, but not limited to, temperature orresistivity of cooling zone and tissue interface, for monitoring andcontrolling operation of catheter. Controller may include indicators fortemperature indicator 231, timer 232 and/or setting for cryosealduration, pressure regulator 233, pressure gauge 234, power switch 235.Parameters can be displayed on a controller screen and/or on a separatedisplay screen such as a computer using specific software. Controllermay also display anchoring member temperature, time, initiation ortermination of anchoring, pressure within cryogenic tubing. Althoughdepicted near controller 23, gas outlet 150 may be located in otherareas.

In another illustrative embodiment of the invention, FIG. 5A depicts aself-anchoring cannula where channel 16 is an operative channel thataccommodates and allows various sliding applicators or guides 41 forcannula guidance and/or tissue operation. The cannula tip end 14comprises the distal lumen opening 160, which is equipped with a valve30. Valve 30 may be a haemostatic valve or be constructed ofself-sealing silicone plug. Any other sealing material which can be usedas a plug is contemplated within the invention. The plug seals thecannula distal end against hydrostatic pressure, but allows passage of aneedle, probe, balloon catheter or any tissue operative instrument knownto those in the art, by way of a slit, for operation. Plug seal 30resiliently closes after removal of instrument. Plug or haemostaticvalve 30 may be located at proximal and/or distal end of lumen 16.

FIG. 5B is a magnification of 41 and illustrates the multi-needleslidable applicator protruding off anchoring tip 14 which is deployed inoperative mode for a better distribution of injectable composition. Theapplicators are constructed and designed to be variable in length aswell as being capable of being deployable in situ. Tip end applicators41 are optionally equipped with sensors 18 and can be used to provideenergy sources, fluids, mechanical devices, guide wires, or the like, tothe tissue. It is contemplated that injection and/or aspiration lumen,such as illustrated in FIG. 1, would add functionality to the anchoringcannula. It is also within the spirit of the invention that retractable,adjustable length, and deployable fluid, balloon catheter or needle,energy and/or operating tip ends and/or mechanical devices may be usedin conjunction with any of the devices embodied within the invention. Ina non-limiting illustrated example, FIG. 5B depicts applicators whichare variable in length. Several of the applicators are positioned withinfrozen margin of a seal 193 while several other applicators areillustrated as extending to unfrozen region 194.

The catheter and lumen are made of plastic, and or composite materialsthat are compatible with critical parameters such as pressure, profile,yield, and compatibility with composition, pushability, flexibility,kink and torque resistance, sterilization and the like. They should alsobe able to incorporate wires and microcomponents such as sensors oroptical systems. A number of materials are available for catheter andthin wall miniature tubing construction, including, but not limited to,polyethylene (PET), nylon, PE (cross linked and other polyolefin),polyurethane, polyvinyl chloride (PVC), and composite-like materials(polyamide/polyurethane composite), polyurethane TECO polymers,poly(tetrafluoroethane) or poly(tetrafluoroethylene) (PTFE), PEBAX,HYTREL, polyimide, and braided polyimide.

Size of catheter or needle: The outer diameter of the shaft 11 couldrange in size, for example, from 0.3 mm for microprocedures, to 2.5 mmfor endoscopic procedures, to 10 mm or more for open surgery procedureor direct procedures through natural openings or surgical cavities. Thelength of the shaft depending on the location of tissue from the bodysurface could be in the range of, for example, 15 cm for easilyaccessible tissue such as the prostate gland to 130 cm or up to 200 cmfor endoscopic procedure to distal lesion of the aerial, or digestivetract. In a needle injector embodiment of FIG. 4A, the cooling zone wasdetermined to have a height of 70 mm, diameter of cooling tip of Fr.3,diameter of adjacent slidable metal needle of 24G, and diameter ofadjacent thermocouple TEFLON wire of 1 mm. All three parts were in closecontact with each other within a PTFE sheath of 2.7 mm diameter. Usingthis prototype inserted into a chicken leg, a digital thermometer Fluke54II (Fluke, USA), and a tissue biocompatible marker (SPOT, GI Supply,Inc, USA), injection procedure was effected at slightly negativetemperature (−3° C.) of the ring-shaped cryoseal to tissue interface,even though freezing point of SPOT is 0° C. Cryogen was CO₂ from ahigh-pressure cylinder. Warming was spontaneous.

In the catheter injector embodiment of FIG. 4A, diameter of distalcooling tip was Fr.8 and height of 10 mm. The injecting tip opening wasat a level of the cooling tip distal end with the metal injecting tubingat 24 G. Injection procedure was possible during warming of indwellingcatheter injector when wall temperature was slightly positive (start +3°C.) and maintained at that level during the rest of the SPOT markerinjection. No backflow of the marker though the entry-track of thecatheter was detected when the cryoseal was “on.” Control testsindicated that backflow was present during injection in the absence ofthe cryoseal. There was no need for injection opening of adjacentinjection tubing 16 of FIG. 4A to be protruding for injection to besuccessful, complete, and without backflow.

Proximal end of operative channel 16 of FIG. 5A may be equipped with ameans to control the depth of penetration of distal end tip 14 andinjection tip end 41. First cannula shaft and injection stem may bearmarkings at known distances, and second valve 30 allows for sliding andadjusting depth of penetration of injection stem off the cannulaindwelling end. It is obvious that during positioning of the catheter,needle or cannula equipped with the retractable inner needle instrumentor device, the inner instrument or device remains retracted duringpositioning and securing of the cannula to the target, which are thendeployed in operative position.

Critical dimensions of the cryoseal: the frozen and/or unfrozenring-like shaped tissue layer created longitudinally and radially alongthe instrument axis and about the cooling zone 152 of injector distalend 14 may vary in size and shape with the thermal field created aboutthe cooling zone. Its height may vary from 0.5 mm to 50 mm, preferablyfrom 1 mm to 30 mm, and more preferably from 5 mm to 10 mm. Itsthickness temperature and structure (among other physicochemicalparameters) may also vary with cooling temperature and duration ofapplication. However, cryothermal and structural change expansion(thickness) into tissue is controllable so that only the anti-backflowand/or the anchoring effect are obtained without any damage or harm tosurrounding tissue. Alternatively lower negative temperatures for thecryoseal or longer duration or activation to the lower temperatures mayentail the growth of large, sizeable frozen/unfrozen volumes. If it isestimated that the indwelling part of the catheter has created anirregular and large entry track, the operator may form a larger frozenring than otherwise would be necessary. However, the preliminaryinjection of inert contacting fluid, such as isotonic saline liquid,into an irregular entry track through injection openings may circumventthe issue and allow for creation of a small self-adjustedfluid-to-tissue biological cryoseal.

Although the cryoseal is made of structured water and tissue componentsat various temperatures that seal and bond the indwelling cooling wallof fixed dimensions to the tissue, the cooling zone of wall 152 may besizeable. For instance, such cooling zone may be that of an inflatablecooling balloon whose interior connects to lumen 15 through a wallopening for the cryogen, and to lumen 150 through a cryogen returnopening. Although the tip end of device 11 is usually cylindrical andstraight any other shape best suited for the intended use, such as suchas pigtail, bent, or curved shape is within the scope of this invention.

In addition, the invention as described herein may also include an outersheath member or guide member. FIGS. 6A, 6B and 6C illustrate anembodiment exemplifying an outer sheath member or guide member 80,coaxially aligned with a multilumen catheter. Although not limiting thesheath to specific uses, it is contemplated that the outer sheath membermay be used for direct injection or circulation of fluids (thermal,chemical, or the like), as an energy delivery probe (thermal energydeposition and/or deprivation, etc), as a needle or sensor guide, as asterile cover for a non-sterile probe, to provide for tissue samplingprior or subsequent to a procedure, or combinations thereof. The outersheath member may also be designed to provide for visualization ofrelative positioning of each element and for assessing depth immersioninto a tissue.

As previously illustrated in FIG. 1A, the multilumen catheter 10 of FIG.6A is comprised of a shaft 11 and an inner lumen 150. Inner lumen 150further contains adjacent multiple lumens (15, 16, 17). The distal endof the catheter member 10 and/or the cryogenically induced region innerand/or outer wall 140 is optionally equipped with a sensing member (notshown). The catheter 10 has fluid aspiration, injection and/or cryogenicfluid dispensing capability through inner lumens 15, 16, 17 and openings170 and 160. Although FIGS. 6A, B and C depict the coaxial, outer sheath80 encompassing the embodiment of FIG. 1, it is contemplated that thesheath may be used with any of the designs illustrated or contemplatedherein. FIG. 6A particularly describes the multilumen catheter retractedwithin the coaxial outer sheath 80. Although FIG. 6A illustrates thesheath having an open end, the sheath may also contain a closed end orgrid-like end. As further illustrated in FIG. 6B, coaxial outer sheathmember 80 has an external surface 81 and internal surface 82. The gapbetween outer surface of the multilumen catheter 10 and the innersurface 82 is adjustable to allow the multilumen catheter 10 to fitinside of the sheath member 80, or for injecting or aspirating fluid(s),cells, and fragments to and from the tissue. Sheath member 80 can bedesigned to contain additional lumens. Cryogenically induced region 19can be made by thermal energy transferred through the catheter andsheath walls when in close contact with each other.

The outer sheath member can be constructed from, or coated with, anymaterial known to one of skill in the art, including thermal conductingmaterials (such as a metallic material or thermoplastic elastomer),plastics (natural, synthetic), porous or non-porous materials, flexibleor rigid materials, or the like as well as a combination of materialsarranged in multiple layers. In a preferred embodiment, the outer sheathmember is made from metallic stainless steel materials. The outer sheathmember material can also be manufactured from any materials that arebiocompatible and that can be sterilized, therefore being used as asterile cover for a non-sterile probe. The outer sheath member can beused as a simple guide for the multilumen catheter device and/or as afluid flow device, having similar capabilities as the multilumencatheter itself. The outer sheath member may also be designed to providevisualization of relative positioning of the outer sheath member, probeand/or the entire fluid flow device relative to each other and forassessing depth immersion into a tissue, through the incorporation ofany type of material known to one of skill in the art which providesvisualization, including ultrasound guidance, radiographic guidance,fluoroscopic guidance, or the like.

The outer sheath member may be manufactured to any thickness necessaryand accommodate any size probes, needles, instruments, including energydeposition or deprivation devices such as resistance, microwave,radiofrequency heating, or the like. The outer sheath member can also bedesigned to contain the same contour or shape of the probe tip, whetherthe tip is pointed, blunt, or any other variations. In a particularembodiment, the outer sheath member is designed to have a thin walland/or allow for use with thin cryogenic needles, such as, but notlimited to, Fr 8 gauge, 1-2 mm sized needles. The outer sheath membercan also be designed to accommodate sensors, such as thermal, impedance,pressure, or the like. In a preferred placement, sensors within thesheath could be positioned within the vicinity of the injection site.Additionally, for optimal heat exchange, the cryogenic probe or needlemay be designed to contain a tight fit with the coaxial outer sheath 80.

FIG. 6C illustrates a portion of the multilumen catheter 10 protrudingfrom coaxial outer sheath member 80. It is contemplated that the outersheath member may be constructed to have any length, or arranged toencompass either the entire multilumen catheter, or any portion thereof.The relative position of the outer sheath member 80 with respect to theprobe can be adjusted by use of systems known to those skilled in theart, such as, but not limited to, use of valves or adaptors such asTouhy-Borst adaptors. Such a system allows incremental adjustment of thesheath in a manner such that a set position is achieved and ismaintained during a procedure. Given that the cryogenic probe isdesigned to move within the outer sheath member 80, the sheath can alsobe constructed from any type of material that maximizes such movement.In addition to being capable of being retracted, the sheath can bedesigned to contain a connecting element 86 to permanently orsemi-permanently connect to a receiving element 88 positioned on anyportion of the fluid flow device thereof. The receiving element 88 isdesigned or manufactured to receive and interconnect with the connectingelement 86. The connecting element could include a nut-and-threadsystem, a twist-on-nut system, clamp system, button release system, orany connector type suitable to the application.

FIG. 6D illustrates protrusion of the multilumen catheter 10 from thecoaxial aligned, outer sheath member 80 with multiple cryogenicallyinduced regions. The multilumen catheter 10 protrudes from the tip end84 of the coaxial aligned, outer sheath member 80. Two cryogenicallyinduced zones 19′ and 19″, produced for example through inner lumen 15′and 15″, respectively, for dispensing cryogenic material, areillustrated along with a side port opening, 161, for fluid delivery intothe tissue located between the two cryogenic zones. As illustrated,cryogenic region 19′ is obtained by the wall of the multilumen catheter10 contacting the tissue while 19″ is obtained through the walls ofmultilumen 10 and outer sheath member 80.

In another embodiment of the invention as illustrated by FIG. 6E, outersheath member 80 contains a cryogenic fluid lumen 22. The figure furtherillustrates the location multiple cryogenic regions, including 19′ andthe cryogenically induced zone 19″ from the cryogenic fluid lumen 86located within outer sheath member 80. A port opening 161 is locatedbetween the tip end 84 of the coaxial aligned, outer sheath member 80and opening 160. The location of the side opening 161 can be adjusted sothat it is set at various distances from 19″ by movement of themultilumen catheter 10. Therefore, the motion, either advancement orretraction, of multilumen catheter 10 within 80 sets various sized gapsbetween 19′ and 19″ and allows for fluid to be injected at variousdistances from 19′ through port 161. By decreasing the gap between 160and 80 during simultaneous cooling of 19′ and 19″ it is further possibleto compress the tissue comprised between the cryogenically inducedzones. Cryogenic zones 19′ and 19″ can be generated at will,simultaneously, at various time intervals, or with adjustable thermalcycles.

A typical mode of operation, such as for percutaneous image-guided solidtumor tissue injection, utilizing the catheter/needle of the instantinvention is as follows:

Tumor characteristics, such as location, shape, structure, relation tostructures or organs, are determined prior to injection so that theguidance technique, the needle path, the type and volume of compositionto be injected are precisely calculated. The composition is prepared andready to use for the indicated procedure.

In the first step, the distal end of the device is guided to tumor site(FIG. 1) with appropriate guiding means. A preferred, but non-limitingmeans includes imaging guidance using Ultrasound with an enhancedechogenicity device using COLORMARK or NUVUE COLORMARK features(NuVueTherapeutics, Inc).

In the second sep, the distal end is embedded into tumor tissue 100through tissue surface 200 at desirable depth and if necessary imaged byan external device 300 such as ultrasound, or assessed by sensors 18.Prior to the insertion of the distal end of the device, if the use of acoaxial outer sheath is required, the sheath, supported by use of atrocar or stylet, is inserted into the intended target tissue area. Ifdesired, the probe itself can also be used as a stylet into the sheath.Upon placement at the desired location, the trocar is removed, leavingthe sheath in place. The device, or the cryoprobe tip of the device, canthen be inserted or guided through the sheath to the desired position,usually a predetermined distance from the injection lumen, proximal ordistal to it. In addition to markings on the probe, the sheath may bedesigned to include any materials known to one of skill in the art whichprovide visualization of the relative position of the probe and sheathposition relative to each other and for assessing the depth of immersioninto the tissue.

The third step of the procedure provides for opening of the cryogenicfluid valve of controller 23 (manual switch, pedal, automated switch) toallow fluid circulation and/or expansion within lumen 150. This resultsin cool down of the wall of indwelling part of injector and creates acooled ring-like zone made of frozen/unfrozen tissue as the walltemperature drops down to the freezing point temperature of the tumor,i.e. in the range of about +4 degrees C. (° C.) to −4° C. or lower,preferably 0° C. to −4° C., or lower. Given that a thin layer ofunfrozen/frozen tissue suffices to create a tight and leak proof bond atthe multilumen/tissue interface, there is no need to make a large frozencryoseal ring when the goal is only to perform an injection oraspiration procedure.

The cryogenically induced region is maintained by adjusting the flow ofthe cryogenic fluid over time so that the cryogenic seal/bond thicknessis sustained. The temperature of the wall to seal interface bond isregulated to desirable wall device temperature for flowing substances(or substance mixture) to the distal end of the injection lumen (i.e.temperature is slightly higher than freezing point of substance, orfreezing point of substance is slightly lower than that of tissue).Substance can also be mixed with low freezing point fluids.

The fourth step includes injection of the composition. Injectioncommences in conjunction with cryoseal formation and is assessed eitherby immobilization of the tip end or ring/tissue temperature measured orcalculated by specific dedicated software, such strength may vary withthe nature and hydration of the target tissue. Injection may be effectedduring cooling and/or warming of the cryoseal as long as the bondtemperature is still strong enough to insure sealing of entry track 101of indwelling multilumen catheter 12.

Depending on tissue characteristics, indication, volume to be injected,patient cooperation and clinical status, injection may be effected atonce and quickly against tissue pressure, lasting only a few seconds,from 1 to 10 seconds. Injection may be effected slowly at low pressureover a period of seconds to minutes. Injection may last over longerperiods if necessary. In any case, the cryoseal is maintained at stableand desirable size for the desirable duration by monitoring andcontrolling its temperature with cooling/warming (spontaneous orartificially controlled) sequences. Sequences are based on “on” and“off” position of cryogenic fluid valve, continuous supply of cryogen atdifferent pressure, or combination of both, or on any other means knownby those of skill in the art.

Injection sites: Injection can be performed within warm, cooled, and/orfrozen tissue, since the device design allows for adjusting the locationof injection openings in relation to tumor characteristics and/orthermal fields. Unlimited injections may be executed within pervioustissue structures and be concurrent to a static or a dynamic cryoseal,i.e., a steady, growing or regressing. It is understood that apreviously impervious structure of the cryoseal may be injected withcomposition when returning to a state of fluid permeability.

In the fifth step, the cryogenically induced region is left to warmand/or melt spontaneously or automatically. The cryoseal may melt assoon as the injection is completed. Upon spontaneous warming, detachmentoccurs when the device becomes movable within the tissue or itstemperature is above its freezing point. It may be desirable to dislodgeand remove the device from the tissue before full melting of thecryoseal. In such a case, warming of the cooling zone may be effected byheating resistance located in the wall of shaft 11, or by closing avalve located on return lumen 150. Such action prevents further cryogenexpansion and permits warm cryogen fluid into lumen 150. Iffractionation of dose or multiple injection sites are a preferred modeof administration, steps 2 to 4 are repeated. If a period is estimatednecessary for administered dose to be distributed or absorbed withintarget tumor, the cryoseal is maintained for such desirable periodwithout further injection.

It is further contemplated that the cryogenic fluid flow can be short induration, alternated with stop flow periods of cool-warm cycles, orcontinuous over variable duration periods to allow for permanentsecuring and positioning of the fluid flow device to the target tissue.It is also contemplated that a sizeable cryogenic seal may have a fluidimpervious structure and/or a damaging structure and/or a damagingstructure for tissue cells or components. By adjusting the temperature(for instances with low boiling point coolant) and duration of thecooling/warming cycle and performing one or multiple cycles thedeleterious effects of the cryoseal can be associated with thephysicochemical effects of the injected fluid-based composition.

Termination of the cryogenically induced region occurs by preventingcryogenic fluid admission and melting the cryogenic seal, or by anyother known means, to allow for fast detachment of the fluid flow devicefrom the cryogenic zone. At termination, the device can be retrievedfrom the tissue.

Permanent seal of entry track: it may be desirable to permanentlyocclude the entry-track of the device after removal. In such caseinjection lumen 16 allows for injecting tissue with sealing agents, suchas but not limited to glue or fibrin glue, during removal of the device.Some sealing agents may be selected from substances that are liquid incold state and solid in warm state.

Aspiration mode: operator effects step 1 to 3, then aspirates tissuefluids and or tissue components through the opening 170 of lumen 17, byway of a mechanism including, but not limited to applying negativepressure at the proximate end of the aspiration lumen.

Tissue washing mode: operator effects steps 1 to 3, then injectscompositions and simultaneously or sequentially aspirates tissuefragments, debris, cells, and fluids.

Alternative use of self-anchoring injector: an alternative use of theinjector of the invention includes manipulation of the tissue ofinterest before or during treatment administration such as but notlimited to techniques of imaging, ablation, injection, or extirpation.

Tissue Ablation. In addition to methods for creating a self-anchoring,it is contemplated that the anti-flow back device which is capable ofinjecting compositions into a treatment site can further be used fortissue ablation methods. Such tissue ablation techniques may includecryogenics and/or injection of various ablation compositions, such asfree drug-solutions or carrier bound drugs.

The apparatus of the invention can be combined with any open accessand/or minimally invasive ablation techniques (high intensity focusedablation (HIFU), microwave, laser light, radiofrequency (RF),cryosurgery, brachytherapy), or loco-regional therapies (embolization,chemoembolization and the like), or systemic therapies (chemotherapies).

All patents and publications mentioned in this specification areindicative of the levels of those skilled in the art to which theinvention pertains. All patents and publications are herein incorporatedby reference to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by reference.

It is to be understood that while a certain form of the invention isillustrated, it is not to be limited to the specific form or arrangementherein described and shown. It will be apparent to those skilled in theart that various changes may be made without departing from the scope ofthe invention and the invention is not to be considered limited to whatis shown and described in the specification and any drawings/figuresincluded herein.

One skilled in the art will readily appreciate that the presentinvention is well adapted to carry out the objectives and obtain theends and advantages mentioned, as well as those inherent therein. Theembodiments, methods, procedures and techniques described herein arepresently representative of the preferred embodiments, are intended tobe exemplary and are not intended as limitations on the scope. Changestherein and other uses will occur to those skilled in the art which areencompassed within the spirit of the invention and are defined by thescope of the appended claims. Although the invention has been describedin connection with specific preferred embodiments, it should beunderstood that the invention as claimed should not be unduly limited tosuch specific embodiments. Indeed, various modifications of thedescribed modes for carrying out the invention which are obvious tothose skilled in the art are intended to be within the scope of thefollowing claims.

The invention claimed is:
 1. A backflow limiting device for delivery ofat least one treating composition to a treatment region of a tissuestructure comprising: a multilumen catheter including at least one firstlumen having a distal end terminating in a substantially non-expandable,circumferential chamber positioned about the inside of said catheter,wherein at least a portion of said chamber is sized and shaped toprovide at least one cryoseal resulting in direct catheter-interstitialtissue interface about a circumference of said catheter at a distancefrom an injecting site, said cryoseal sized and shaped to seal saidcatheter directly to said tissue without the need of a pressurizedballoon to initiate tissue adherence which is effective to minimize orprevent backflow of at least one treating composition back along acatheter entry track, said lumen in fluid connection with at least onecryogenic source effective for lowering at least a portion of saidtissue structure to a temperature at or about the tissue freezing pointto form said cryoseal, and at least one second lumen in fluidcommunication with a treating composition source and having a deliveryend adapted for delivery of said at least one treating composition to aninterstitial space within a tissue structure, said delivery endpositioned a distance from said cryoseal to allow administration of saidat least one treating composition to said tissue at a location which isdistal from said cryoseal; said multilumen catheter being constructedand arranged for injecting said at least one composition to a treatmentregion within said tissue structure prior to, subsequent to, orconcurrently with formation of said cryoseal; and an outer sheath memberhaving a substantially continuous side wall and a main lumen sized andshaped to be coaxially aligned with said multilumen catheter; wherebysaid at least one cryoseal formed proximal to said treatment region iseffective to minimize or prevent backflow of said treating composition.2. The backflow limiting device according to claim 1 wherein saidsubstantially continuous side wall contains at least one lumen containedwithin said side wall and terminating in a chamber, said side wall lumenconstructed and arranged for delivering said at least one cryogenicsource for forming a cryoseal independent of said catheter, receiving adevice for administering said treating composition or forming acryoseal, or combinations thereof.
 3. The backflow limiting deviceaccording to claim 2 wherein said outer sheath member contains at leastone device for forming a cryoseal, administering at least one a treatingcomposition, aspirating a tissue fluid, or combinations thereof.
 4. Thebackflow limiting device according to claim 1 wherein said outer sheathmember slideably engages said multilumen catheter whereby the relativeposition of said outer sheath member with respect to said multilumencatheter can be adjusted.
 5. The backflow limiting device according toclaim 1 wherein said outer sheath member is made of thermal conductingmaterials, plastics, porous materials, non-porous materials, flexiblematerials, rigid materials, or combinations thereof.
 6. The backflowlimiting device according to claim 1 wherein said outer sheath membercontains an open end.
 7. The backflow limiting device according to claim1 wherein said treating composition is selected from the groupconsisting of saline solution, heating or cooling fluids, aphotosensitizer, a radiosensitizer, a radioisotope, a sclerosing agent,radioseeds, thermoseeds, glue, a vaccine, a gene, a gene vector,biologically active peptides, proteins, an immunologic factor, ahormone, a cytotoxic agent, free or encapsulated drugs, and combinationsthereof.
 8. The backflow limiting device according to claim 1 furtherincluding sensors for sensing tissue parameters selected from the groupconsisting of electrical impedance, temperature, pressure, opticalcharacteristics and combinations thereof.
 9. The backflow limitingdevice according to claim 1 wherein said multilumen catheter furtherincludes at least one lumen for aspiration of tissue fluids, cells orother compositions.
 10. The backflow limiting device according to claim1 wherein at least one lumen slidably engages the outer surface of saidmultilumen catheter and is in parallel arrangement with said lumen forsupplying of cryogenic material.
 11. The backflow limiting deviceaccording to claim 1 wherein at least one lumen further contains atleast one variable length applicator and/or needle.
 12. The backflowlimiting device according to claim 11 wherein said at least one variablelength applicator and/or needle is deployable in situ.
 13. The backflowlimiting device according to claim 11 wherein said variable lengthapplicator and/or needle further includes at least one sensor forsensing tissue parameters selected from the group consisting ofelectrical impedance, temperature, pressure, optical characteristics andcombinations thereof.
 14. The backflow limiting device according toclaim 1 wherein said device further includes means for providing asource of interstitial energy to said treatment region selected from thegroup consisting of cryothermal energy, sonic, light, electroporation,radio-frequency energy, and combinations thereof.
 15. The backflowlimiting device according to claim 1 wherein said cryoseal forms aring-shaped structure of frozen and semi-frozen tissue longitudinallyand radailly arranged about said catheter.